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4 '-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

Jeong, S. Y., Hogarth, P., Placzek, A., Gregory, A. M., Fox, R., Zhen, D., Hamada, J., van der Zwaag, M., Lambrechts, R., Jin, H., Nilsen, A., Cobb, J. S., Pham, T., Gray, N., Ralle, M., Du, M., Schwanemann, L., Rai, P., Freed, A., Wakeman, K., Woltjer, R. L., Sibon, O. C. M. & Hayflick, S. J., 29-Oct-2019, In : EMBO Molecular Medicine. 11, 17 p., e10489.

Research output: Contribution to journalArticleAcademicpeer-review

Pantothenate kinase-associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease-vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4 '-phosphopantetheine, normalized levels of the CoA-, iron-, and dopamine-related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4 '-phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron-sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4 '-phosphopantetheine as a candidate therapeutic for PKAN.

Original languageEnglish
Article numbere10489
Number of pages17
JournalEMBO Molecular Medicine
Volume11
Publication statusPublished - 29-Oct-2019

    Keywords

  • 4 '-phosphopantetheine, coenzyme A, NBIA, PANK2, PKAN, KINASE-ASSOCIATED NEURODEGENERATION, FATTY-ACID SYNTHESIS, ACYL CARRIER PROTEIN, COENZYME-A, MITOCHONDRIAL IRON, PANTOTHENATE, GENE, ACCUMULATION, BIOGENESIS

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